Abstract:

The present invention relates to novel platensimycin derivatives, their
intermediates and preparing methods of the same. Platensimycin is known
as an effective antibiotic material having a broad antimicrobial spectrum
and its derivatives are also expected to be effective antibiotic
candidates. The present invention also relates to a novel preparing
method of platensimycin. The intermediates used for the production of
platensimycin and its derivatives of the present invention are tricyclo
ketone derivatives and tetracyclo derivatives. Tetracyclo derivatives are
prepared from tricyclo ketone derivatives prepared by carbonyl ylide
[3+2] cycloaddition of dia-zoketone derivative.

5. The method for producing platensimycin represented by formula 2 and its
derivatives according to claim 3, wherein enone derivative represented by
formula 5 is prepared by the following steps:5-1) inducing dehalogenation
of tricyclo ketone derivative represented by formula 10 to give the
compound represented by formula 10-1;5-2) reacting the compound
represented by formula 10-1 with dimethyl 2-oxopropylphosphonate to give
enone compound represented by formula 11-1;6) inducing hydrosilylation of
the compound represented by formula 10-1 in the presence of ruthenium(I)
catalyst, followed by reducing thereof to diisobutylaluminum hydride or
diisopropylaluminum hydride, or reacting the said compound with organic
lithium (R5-Li; R5=(C1-C10)alkyl or (C6-C20)aryl), followed by
hydrolyzing thereof to give the compound represented by formula 12-1;7)
inducing intramolecular condensation of the compound represented by
formula 12-1 to give tetracyclo derivative represented by formula 4-1;
and8) inducing methylation of tetracyclo derivative represented by
formula 4-1 to give enone derivative represented by formula 5-1.
##STR00062## [In formulas 4-1, 5-1, 10, 11-1 and 12-1, R1 is iodo,
bromo or chloro; R2, R3 and R5 are independently H,
(C1-C10)alkyl or (C6-C20)aryl; R4 is H, (C1-C10)alkyl, (C6-C20)aryl
or (C6-C20)aryl(C1-C10)alkyl.]

6. The preparing method of platensimycin and its derivatives represented
by formula 2 according to claim 3, wherein the enone derivative
represented by formula 6, in which R5 is (C1-C10)alkyl or
(C6-C20)aryl, is prepared by the following steps:9) reacting CuI and
organic lithium (R5--Li; R.sub.5.dbd.(C1-C10)alkyl or (C6-C20)aryl),
to which the compound represented by formula 6-1 and
tri(C1-C10)alkylsilyl chloride are added to give the compound represented
by formula 6-2; and10) inducing oxidation and de-protection of the
compound represented by formula 6-2 in the presence of DDQ
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and HMDS
(hexamethyldisilazide) to give the compound represented by formula 6.
##STR00063## [In formulas 6, 6-1 and 6-2, R1 is H, (C1-C10)alkyl,
iodo, bromo or chloro; R2 and R3 are independently H,
(C1-C10)alkyl or (C6-C20)aryl; R4 is H, (C1-C10)alkyl, (C6-C20)aryl
or (C6-C20)aryl(C1-C10)alkyl; R5 is (C1-C10)alkyl or (C6-C20)aryl; Y
is tri(C1-C10)alkylsilyl.]

7. The preparing method of platensimycin and its derivatives represented
by formula 2 according to claim 4, wherein the tricyclo ketone derivative
represented by formula 10 is prepared by the following steps:11) reacting
the compound represented by formula 16 and allyl derivative represented
by formula 17 in the presence of sodium hydride, followed by hydrolysis
and reaction with diazomethane to give diazoketone derivative represented
by formula 13; and12) inducing carbonyl ylide [3+2] cycloaddition of
diazoketone derivative represented by formula 13 in the presence of
rhodium catalyst to give tricyclo ketone derivative represented by
formula 10. ##STR00064## [In formulas 10, 13, 16 and 17, R1 is
(C1-C10)alkyl, iodo, bromo or chloro; R2 and R3 are
independently H, (C1-C10)alkyl or (C6-C20)aryl; R4 is H,
(C1-C10)alkyl, (C6-C20)aryl or (C6-C20)aryl(C1-C10)alkyl; X is iodo,
bromo or chloro.]

17. A preparing method of diazoketone derivative represented by formula 13
comprising the following steps:13) reacting ethyl cyanoacetate
represented by formula 14 and carbonyl chloride compound represented by
formula 15 in the presence of sodium (C1-C10)alkoxide to give the
compound represented by formula 16;14) reacting the compound represented
by formula 16 and allyl derivative represented by formula 17 in the
presence of sodium hydride, followed by hydrolysis to give the compound
represented by formula 18; and15) reacting the compound represented by
formula 18 and diazomethane to give diazoketone derivative represented by
formula 13. ##STR00068## [In formulas 13 and 15 to 18, R1 is
(C1-C10)alkyl, iodo, bromo or chloro; R2 and R3 are
independently H, (C1-C10)alkyl or (C6-C20)aryl; R4 is H,
(C1-C10)alkyl, (C6-C20)aryl or (C6-C20)aryl(C1-C10)alkyl; X is iodo,
bromo or chloro.]

Description:

TECHNICAL FIELD

[0001]The present invention relates to novel platensimycin derivatives
represented by formula 1 and a preparing method of the same. The present
invention also relates to a novel preparing method of platensimycin.
Platensimycin is known as a useful antibiotic having a wide antimicrobial
spectrum and its derivatives are also expected to be useful antibiotics.

##STR00001##

[0002]The present invention relates to intermediates for the production of
platensimycin and its derivatives and a preparing method of the same,
more precisely tricyclo ketone derivatives represented by formula 10 or
formula 24 and a preparing method of the same and a preparing method of
tetracyclo derivatives represented by formula 4 or formula 19. Tricyclo
ketone derivatives are produced from diazoketone derivatives via carbonyl
ylide [3+2] cycloaddition reaction. Tetracyclo derivatives are important
intermediates for the production of platensimycin and its derivatives,
which are produced from tricyclo ketone derivatives, the starting
material.

[0005]Platensimycin is a novel antibiotic having a wide antimicrobial
spectrum, which has been isolated from Streptomyces platensis, a kind of
fungi found in the soil of South Africa by Merck Co., USA.

##STR00004##

[0006]In the past decades, novel antibiotics kept being discovered from
nature and in the laboratory. But human defense system against infection
has been consistently compromised. Microbes keep developing resistance
against the conventional antibiotics. Multi-drug resistant bacteria bring
serious infection problems; and particularly hospital acquired
(nosocomial) infection is more serious. In-patients are weak, and they
are more easily infected. Once they are infected, it is very difficult to
treat the infection with drugs and it might even result in death.

[0007]Therefore, development of new drugs having completely different
physiological mechanisms to attack pathogens is required. Platensimycin
isolated from the fungus Streptomyces platensis is one of them.

[0008]Platensimycin is a selective intracellular lipid synthesis
inhibitor, which works on β-ketoacyl-(acyl-carrier-protein (ACP))
synthase I/II (FabF/B) to inhibit lipid synthesis. It was confirmed from
the X-ray crystallographic studies that platensimycin targets the
modified structure resulted from acylation of the lipogenic enzyme
FabF/B. The mechanism of platensimycin is different from those of the
conventional antibiotics being used clinically.

[0009]In the laboratory, chemists try to establish total synthesis routes
to new compounds. In total synthesis, a complex compound is prepared from
simple materials by using organic chemistry knowledge. For development of
a new drug from a natural substance, investigation of structure-activity
correlation is necessary. And then synthetic routes should be found for
large scale preparation of the final target compound from less expensive
starting materials. Total synthesis of platensimycin was first
accomplished by Prof. Nicolau's research team at the Scripps Research
Institute.

[0011]Platensimycin derivatives may be designed by introducing different
substituents in the backbone of platensimycin itself. They are good
candidates as promising antibiotics by inhibiting fatty acid synthesis in
bacteria. A good scheme for efficient total synthesis of platensimycin
should also allow facile preparation of wide variety platensimycin
derivatives for bioassay.

DISCLOSURE OF INVENTION

Technical Problem

[0012]The present invention relates to novel platensimycin derivatives
represented by formula 1 and a preparing method of the same. The present
invention also relates to a novel preparing method of platensimycin.
Platensimycin is known to have a broad antimicrobial spectrum, so that it
has been known as an effective antibiotic material. And thus, its
derivatives are also expected to be effective antibiotic candidates.

[0013]Platensimycin derivatives represented by formula 1 include those
platensimycin derivatives retaining backbone structure of the informed
platensimycin but having diverse substituents introduced therein and
isoplatensimycin and its derivatives maintaining backbone structure of
the said platensimycin.

[0027]4) de-protecting the protection group of ester compound represented
by formula 9 by using TASF reagent
[((CH3)2N)3S]+[F2Si(CH3)3].sup.- to
give platensimycin and its derivatives represented by formula 2.

[0031]6-1) inducing hydrosilylation of enone compound represented by
formula 11 in the presence of ruthenium (I) catalyst, which is reduced
into diisobutylaluminum hydride or diisopropylaluminum hydride, followed
by hydrolysis to give ketoaldehyde compound represented by formula 12;

[0037]6-2) inducing hydrosilylation of enone compound represented by
formula 11 in the presence of ruthenium(I) catalyst, to which organic
lithium (R5--Li; R5═(C1-C10)alkyl or (C6-C20)aryl) is
added, followed by hydrolysis to give diketone compound represented by
formula 12;

[0044]6) inducing hydrosilylation of the compound represented by formula
10-1 in the presence of ruthenium(I) catalyst, followed by reducing
thereof to diisobutylaluminum hydride or diisopropylaluminum hydride, or
reacting the said compound with organic lithium (R5-Li;
R5═(C1-C10)alkyl or (C6-C20)aryl), followed by hydrolyzing thereof to
give the compound represented by formula 12-1;

[0045]7) inducing intramolecular condensation of the compound represented
by formula 12-1 to give tetracyclo derivative represented by formula 4-1;
and

[0048]When the substituent R5 of enone derivative represented by
formula 6 is H, which is used as the starting material, the substituent
R5 of enone derivative represented by formula 6 can be substituted
with (C1-C10)alkyl or (C6-C20)aryl by the following steps:

[0049]9) reacting CuI and organic lithium (R5--Li;
R5═(C1-C10)alkyl or (C6-C20)aryl), to which the compound
represented by formula 6-1 and tri(C1-C10)alkylsilyl chloride are added
to give the compound represented by formula 6-2; and

[0050]10) inducing oxidation and de-protection of the compound represented
by formula 6-2 in the presence of DDQ
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and HMDS
(hexamethyldisilazide) to give the compound represented by formula 6.

[0052]Tricyclo ketone derivative represented by formula 10 is prepared by
the following steps:

[0053]11) reacting the compound represented by formula 16 and allyl
derivative represented by formula 17 in the presence of sodium hydride,
followed by hydrolysis and reaction with diazomethane to give diazoketone
derivative represented by formula 13; and

[0056]The rhodium catalyst used herein is preferably selected from the
group consisting of rhodium(II) acetate (Rh2(OAc)4) and
rhodium(II) trifluoroacetate [(CF3COO)2Rh]2). The
preferable concentration of the rhodium catalyst is 2-5 mol %. If the
concentration is less than 2 mol % or more than 5 mol %, yield will be
reduced, indicating economically inefficiency.

[0063]4) de-protecting the protection group of ester compound represented
by formula 23 by using TASF reagent
[(CH3)2N)3S]+[F2Si(CH3)3].sup.- to
give isoplatensimycin and its derivatives represented by formula 3.

[0067]6-1) inducing hydrosilylation of enone compound represented by
formula 25 in the presence of ruthenium(I) catalyst, which is reduced
into diisobutylaluminum hydride or diisopropylaluminum hydride, followed
by hydrolysis to give ketoaldehyde compound represented by formula 26;

[0073]6-2) inducing hydrosilylation of enone compound represented by
formula 25 in the presence of ruthenium(I) catalyst, to which organic
lithium (R10--Li; R10═(C1-C10)alkyl or (C6-C20)aryl) is
added, followed by hydrolysis to give diketone compound represented by
formula 26;

[0077]When the substituent R10 of enone derivative represented by
formula 21 is H, which is used as the starting material, the substituent
R10 of enone derivative represented by formula 21 can be substituted
with (C1-C10)alkyl or (C6-C20)aryl by the following steps:

[0078]9) reacting CuI and organic lithium (R10--Li;
R10═(C1-C10)alkyl or (C6-C20)aryl), to which the compound
represented by formula 21-1 and tri(C1-C10)alkylsilyl chloride are added
to give the compound represented by formula 21-2; and

[0079]10) inducing oxidation and de-protection of the compound represented
by formula 21-2 in the presence of DDQ
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and HMDS
(hexamethyldisilazide) to give the compound represented by formula 21.

[0081]Tricyclo ketone derivative represented by formula 24 is prepared by
the following steps:

[0082]11) reacting the compound represented by formula 29 and allyl
derivative represented by formula 30 in the presence of sodium hydride,
followed by hydrolysis and reaction with diazomethane to give diazoketone
derivative represented by formula 27; and

[0085]The rhodium catalyst used herein is preferably selected from the
group consisting of rhodium(II) acetate (Rh2(OAc)4) and
rhodium(II) trifluoroacetate [(CF3COO)2Rh]2). The
preferable concentration of the rhodium catalyst is 2-5 mol %. If the
concentration is less than 2 mol % or more than 5 mol %, yield will be
reduced, indicating economically inefficiency.

[0088]The present invention also relates to tricyclo ketone derivative
represented by formula 10 or formula 24 and a preparing method of the
same, in which tricyclo ketone derivative is characteristically prepared
from diazoketone derivative by carbonyl ylide [3+2] cycloaddition.

[0096]The rhodium catalyst used herein is preferably selected from the
group consisting of rhodium(II) acetate and rhodium(II) trifluoroacetate.
The preferable concentration of the rhodium catalyst is 2-5 mol %. If the
concentration is less than 2 mol % or more than 5 mol %, yield will be
reduced, indicating economically inefficiency.

[0097]Diazoketone derivative represented by formula 13 is prepared by the
following steps:

[0098]13) reacting ethyl cyanoacetate represented by formula 14 and
carbonyl chloride compound represented by formula 15 in the presence of
sodium (C1-C10)alkoxide to give the compound represented by formula 16;

[0099]14) reacting the compound represented by formula 16 and allyl
derivative represented by formula 17 in the presence of sodium hydride,
followed by hydrolysis to give the compound represented by formula 18;
and

[0104]14) reacting 2-methyl-2-propanethiol, the lactone compound
represented by formula A prepared above and DMP (Dess-Martin periodinane)
stepwise in the presence of trimethylaluminum to give thioester compound
represented by formula B; and

[0107]Diazoketone derivative represented by formula 27 is prepared by the
following steps:

[0108]13) reacting ethyl cyanoacetate represented by formula 14 and
carbonyl chloride compound represented by formula 28 in the presence of
sodium (C1-C10)alkoxide to give the compound represented by formula 29;

[0109]14) reacting the compound represented by formula 29 and allyl
derivative represented by formula 30 in the presence of sodium hydride,
followed by hydrolysis to give the compound represented by formula 31;
and

[0111][In formulas 27 to 31, R6, R7, R8 and R9 are the
same as defined in formula 24; X is iodo, bromo or chloro.]

[0112]The present invention also relates to tetracyclo derivative
represented by formula 4 which plays an important role in the production
of the antibiotic platensimycin as a major intermediate, in which
tricyclo ketone derivative represented by formula 10 is
characteristically used to give tetracyclo derivative represented by
formula 4 according to the following steps:

[0114]6) inducing hydrosilylation of enone compound represented by formula
11 in the presence of ruthenium(I) catalyst, which is reduced into
diisobutylaluminum hydride or diisopropylaluminum hydride or reacted with
organic lithium (R5--Li; R5═(C1-C10)alkyl or (C6-C20)aryl)
followed by hydrolysis to give the compound represented by formula 12;
and

[0117]In step 6), the compound represented by formula 12 prepared by the
processes of hydrosilylation; reduction into diisobutylaluminum hydride
or diisopropylaluminum hydride; and hydrolysis is keto aldehyde compound,
in which the substituent R5 is H. In the meantime, in step 6), the
compound represented by formula 12 prepared by the processes of
hydrosilylation; reaction with organic lithium (R5--Li;
R5═(C1-C10)alkyl or (C6-C20)aryl); and hydrolysis is diketone
compound, in which the substituent R5 is (C1-C10)alkyl or
(C6-C20)aryl.

[0118]The present invention also relates to tetracyclo derivative
represented by formula 19 which plays an important role in the production
of isoplatensimycin as a major intermediate, in which tricyclo ketone
derivative represented by formula 24 is characteristically used to give
tetracyclo derivative represented by formula 19 according to the
following steps:

[0120]6) inducing hydrosilylation of enone compound represented by formula
25 in the presence of ruthenium(I) catalyst, which is reduced into
diisobutylaluminum hydride or diisopropylaluminum hydride or reacted with
organic lithium (R10--Li; R10═(C1-C10)alkyl or
(C6-C20)aryl), followed by hydrolysis to give the compound represented by
formula 26; and

[0123]In step 6), the compound represented by formula 26 prepared by the
processes of hydrosilylation; reduction into diisobutylaluminum hydride
or diisopropylaluminum hydride; and hydrolysis is keto aldehyde compound,
in which the substituent R5 is H. In the meantime, in step 6), the
compound represented by formula 26 prepared by the processes of
hydrosilylation; reaction with organic lithium (R10--Li;
R10═(C1-C10)alkyl or (C6-C20)aryl); and hydrolysis is diketone
compound, in which the substituent R10 is (C1-C10)alkyl or
(C6-C20)aryl.

[0124]The preparing method of diazoketone derivative represented by
formula 13 is illustrated in reaction formula 3 and the preparing method
of tetracyclo derivative represented by formula 4 is illustrated in
reaction formula 4.

[0134]Practical and presently preferred embodiments of the present
invention are illustrative as shown in the following Examples.

[0135]However, it will be appreciated that those skilled in the art, on
consideration of this disclosure, may make modifications and improvements
within the spirit and scope of the present invention.

[0136]General Information

[0137]1H- and 13C-NMR spectra were obtained on a Bruker DPX-300
(300 MHz), a Bruker Avance-600 (600 MHz), or a Varian/Oxford As-500 (500
MHz) spectrophotometer. Chemical shift values were recorded as parts per
million relative to tetramethylsilane as an internal standard unless
otherwise indicated, and coupling constants in Hertz. Mass spectra were
recorded on a JEOL JMS 600W spectrometer using electron impact (EI) or
chemical ionization (CI) methods, and a JEOL JMS AX505WA spectrometer
using fast atom bombardment (FAB) method. Significant fragments are
reported in the following fashion: m/z (relative intensity).

[0139]Unless otherwise specified, all reactions were conducted under a
slight positive pressure of dry nitrogen. The usual work-up refers to
washing the quenched reaction mixture with brine, drying the organic
extracts over anhydrous MgSO4 and evaporating under reduced pressure
using a rotary evaporator.

[0140]Solvents used in the reactions were dried under nitrogen atmosphere.
THF was distilled from Na-benzophenone, and CH2Cl2 was
distilled from P2O5. Benzene was washed with conc.
H2SO4, distilled from Na-benzophenone, and stored over 4
molecular sieves. Et2O was distilled from LAH. CH3CN was
distilled from CaH2 and stored over 4 Å molecular sieves.
Pyridine and TEA was distilled over KOH and stored over 4 Å molecular
sieves.

EXAMPLE 1 to 8

Preparation of Intermediates

EXAMPLE 1

Preparation of Diazoketone (C)

##STR00037##

[0141]Preparation of Lactone (A)

[0142]Isopropyl cyanoacetate (0.5 g, 3.9 mmol) was slowly added to a
solution of sodium hydride (60% dispersion in mineral oil, 157 mg, 3.9
mmol) in THF (16 mL) at 0° C. The mixture was stirred for 10 min
before addition of (S)-propylene oxide (purchased from Aldrich, 0.27 mL,
3.9 mmol). After heating under reflux for 6 h, the mixture was cooled to
r.t. and an other portion of (S)-propylene oxide (0.27 mL, 3.9 mmol) was
added to the mixture. The mixture was further refluxed for 6 h then
cooled to 0° C. (E)-Iodoallyl iodide (1.6 g, 5.4 mmol) in THF (3
mL) was slowly added to the mixture. After stirring at r.t. for 30 min,
the mixture was diluted with Et2O (200 mL) before addition of 1 N
HCl (20 mL). The organic phase was washed with brine (30 mL), dried over
MgSO4, filtered and concentrated. The residue was purified by flash
column chromatography (hexanes-EtOAc, 5:1) to give lactone (A) (726 mg,
63%).

[0146]Thioester (B) (443 mg, 1.17 mmol) was dissolved in MeOH (6 mL) and 1
N KOH solution (2 mL) was added to the solution at 0° C. The
reaction mixture was stirred for 10 min at r.t. and treated slowly with 1
N HCl (3 mL) at 0° C. After extraction with EtOAc (30 mL×2),
the organic phase was washed with brine (5 mL×2), dried over
MgSO4, filtered and concentrated.

[0147]TEA (0.20 mL, 1.40 mmol) was added to the solution of the residue
was in Et2O (15 mL) at -20° C. and the mixture was treated
with isobutyl chloroformate (0.17 mL, 1.29 mmol). After 30 min, an
ethereal solution of diazomethane, which was prepared by the reaction of
Diazald (1.5 g, 7.1 mmol) with KOH (1.5 g, 27 mmol), was slowly added to
the reaction mixture, and the mixture was allowed to warm to 0° C.
After stirring the reaction mixture for 4 h, excess diazomethane was
decomposed by careful addition of acetic acid. The reaction mixture was
filtered through a short column of silicagel with the aid of Et2O
and concentrated. The residue was purified by flash column chromatography
(hexanes-EtOAc, 4:1) to provide enantiomerically enriched diazoketone (C)
(337 mg, 88%, two steps). [α]25D -212.0 (c 0.50,
CHCl3).

[0153]Methyl ester (D-1) (2.0 g, 6.2 mmol) was dissolved in MeOH (30 mL)
and 1 N KOH solution (15 mL) was added to the solution at 0° C.
The reaction mixture was stirred for 10 min at r.t. and treated slowly
with 2 N HCl (8 mL) at 0° C. After extraction with EtOAc (100
mL×2), the organic phase was dried over MgSO4, filtered and
concentrated. The residue was dissolved in toluene (10 mL) and evaporated
to provide the crude acid (D-2) (1.9 g, quant.) which was used in the
next step without further purification.

[0154]TEA (1.1 mL, 7.4 mmol) was added to the solution of the crude acid
(D-2)(1.9 g, 6.2 mmol) in THF (60 mL) at -20° C. and the mixture
was treated with isobutyl chloroformate (1.1 mL, 6.8 mmol). After 30 min,
an ethereal solution of diazomethane, which was prepared by the reaction
of Diazald (8.0 g, 38 mmol) with KOH (8.0 g, 143 mmol), was slowly added
to the reaction mixture, and the mixture was allowed to warm to 0°
C. After stirring the reaction mixture for 4 h, excess diazomethane was
decomposed by careful addition of acetic acid. The reaction mixture was
filtered through a short column of silicagel with the aid of Et2O
and concentrated. The residue was purified by flash column chromatography
(hexanes-EtOAc, 4:1) to provide diazoketone (C)(1.8 g, 88%, two steps).

[0159]Methyl ester (D-3) (1.0 g, 5.1 mmol) was dissolved in MeOH (30 mL)
and 1N KOH solution (15 mL) was added to the solution at 0° C. The
reaction mixture was stirred for 10 min at r.t. and treated slowly with 2
N HCl (8 mL) at 0° C. After extraction with EtOAc (100
mL×2), the organic phase was dried over MgSO4, filtered and
concentrated. The residue was dissolved in toluene (10 mL) and evaporated
to provide the crude acid (D-4) (930 mg, quant.) which was used in the
next step without further purification.

[0160]TEA (0.93 mL, 6.6 mmol) was added to the solution of the crude acid
(D-4) (930 mg, 5.1 mmol) in Et2O (51 mL) at 0° C. and the
mixture was treated with isobutyl chloroformate (0.79 mL, 6.1 mmol).
After 30 min, an ethereal solution of diazomethane, which was prepared by
the reaction of Diazald (6.6 g, 31 mmol) with KOH (6.6 g, 118 mmol), was
slowly added to the reaction mixture, and the mixture was allowed to warm
to r.t. After stirring the reaction mixture for 4 h, the flask was cooled
in an ice bath and excess diazomethane was decomposed by careful addition
of acetic acid. The reaction mixture was filtered through a short column
of silicagel with the aid of Et2O and concentrated. The residue was
purified by flash column chromatography (hexanes-EtOAc, 4:1) to provide
diazoketone (E)(863 mg, 70%, two steps).

[0163]3 mol % Rh2(OAc)4 was added to a solution of a diazoketone
(C) (300 mg) in CH2Cl2 (52 mL). After stirring for 10 h, the
mixture was filtered through a short column of silica gel with the aid of
hexanes-EtOAc (1:1) to remove the catalyst, and the filtrate was
concentrated in vacuo. The residue was purified by flash column
chromatography (hexanes-acetone-CH2Cl2, 4:1:1) to provide
ketone (F) as a mixture of keto and hydrate forms (228 mg, 83%).

[0166]3 mol % Rh2(OAc)4 was added to a solution of a diazoketone
(G) (74 mg) in CH2Cl2 (52 mL). After stirring for 10 h, the
mixture was filtered through a short column of silica gel with the aid of
hexanes-EtOAc (1:1) to remove the catalyst, and the filtrate was
concentrated in vacuo. The residue was purified by flash column
chromatography (hexanes-acetone-CH2Cl2, 4:1:1) to provide
ketone (H) as a mixture of keto and hydrate forms (55 mg, 82%).

[0178]Rh2(TFA)4 (17 mg, 0.026 mmol) was added to a solution of
diazoketone (E) (100 mg, 0.52 mmol) in CH2Cl2 (52 mL). After
stirring for 10 h, the reaction mixture was filtered through a short
column of silica gel with the aid of hexanes-EtOAc (1:1) to remove the
catalyst, and the filtrate was concentrated in vacuo. The residue was
purified by flash column chromatography
(hexanes-acetone-CH2Cl2, 4:1:1) to provide ketone (M) (74 mg,
80%).

[0202]KOH solution (10 mL) was added to the solution at 0° C. The
reaction mixture was stirred for 10 min at r.t. and treated slowly with 2
N HCl (10 mL) at 0° C. After extraction with EtOAc (100
mL×2), the organic phase was dried over MgSO4, filtered and
concentrated. The residue was dissolved in toluene (10 mL) and evaporated
to provide the crude acid (2c) (570 mg, quant.) which was used in the
next step without further purification.

[0203]TEA (0.61 mL, 4.4 mmol) was added to the solution of the crude acid
(2c) (570 mg, 2.9 mmol) in THF (15 mL) at -20° C. and the mixture
was treated with isobutyl chloroformate (0.53 mL, 4.1 mmol). After 30
min, an ethereal solution of diazomethane, which was prepared by the
reaction of Diazald (3.8 g, 17 mmol) with KOH (3.8 g, 68 mmol), was
slowly added to the reaction mixture, and the mixture was allowed to warm
to 0° C. After stirring the reaction mixture at 0° C. for 2
h, excess diazomethane was decomposed by careful addition of acetic acid.
The reaction mixture was filtered through a short column of silica gel
with the aid of Et2O and concentrated. The residue was purified by
flash column chromatography (hexanes-EtOAc, 4:1) to provide diazoketone
(2d) (563 mg, 89%, two steps, E:Z=5:1). Rf 0.38 (hexanes-EtOAc,
2:1).

Preparation of Enone (2f)

[0204]Rh2(OAc)4 (34 mg, 0.077 mmol) was added to a solution of
diazoketone (2d) (560 mg, 2.6 mmol) in CH2Cl2 (250 mL). After
stirring for 10 h, the reaction mixture was filtered through a short
column of silica gel with the aid of hexanes-EtOAc (1:1) to remove the
catalyst, and the filtrate was concentrated in vacuo. The residue was
purified by flash column chromatography
(hexanes-acetone-CH2Cl2, 4:1:1) to provide ketone (2e) (270 mg,
55%). Rf 0.21 (hexanes-acetone-CH2Cl2, 4:1:1).

[0241]Methyl ester (4a) (1.1 g, 5.1 mmol) was dissolved in MeOH (30 mL)
and 1 N KOH solution (15 mL) was added to the solution at 0° C.
The reaction mixture was stirred for 10 min at r.t. and treated slowly
with 2 N HCl (8 mL) at 0° C. After extraction with EtOAc (100
mL×2), the organic phase was dried over MgSO4, filtered and
concentrated. The residue was dissolved in toluene (10 mL) and evaporated
to provide the crude acid (4b) (1.0 g, quant.) which was used in the next
step without further purification.

[0242]TEA (1.1 mL, 7.7 mmol) was added to the solution of the crude acid
(4b) (1.0 g, 5.1 mmol) in THF (25 mL) at -20° C. and the mixture
was treated with isobutyl chloroformate (0.98 mL, 7.7 mmol). After 30
min, an ethereal solution of diazomethane, which was prepared by the
reaction of Diazald (6.6 g, 31 mmol) with KOH (6.6 g, 118 mmol), was
slowly added to the reaction mixture, and the mixture was allowed to warm
to 0° C. After stirring the reaction mixture for 1 h, excess
diazomethane was decomposed by careful addition of acetic acid at
0° C. The reaction mixture was filtered through a short column of
silica gel with the aid of Et2O and concentrated. The residue was
purified by flash column chromatography (hexanes-EtOAc, 4:1) to provide
diazoketone (4c) (770 mg, 69%, two steps).

[0244]Rh2(OAc)4 (46 mg, 0.10 mmol) was added to a solution of
diazoketone (4c) (770 mg, 3.4 mmol) in CH2Cl2 (350 mL). After
stirring for 10 h, the reaction mixture was filtered through a short
column of silica gel with the aid of hexanes-EtOAc (1:1) to remove the
catalyst, and the filtrate was concentrated in vacuo. The residue was
purified by flash column chromatography
(hexanes-acetone-CH2Cl2, 4:1:1) to provide ketone (4d) (610 mg,
90%).

[0293]Ester (7c) (910 g, 2.4 mmol) was dissolved in MeOH (15 mL) and 1 N
KOH solution (4.7 mL) was added to the solution at 0° C. The
reaction mixture was stirred for 10 min at r.t. and treated slowly with 2
N HCl (2.4 mL) at 0° C. After extraction with EtOAc (100
mL×2), the organic phase was dried over MgSO4, filtered and
concentrated. The residue was dissolved in toluene (10 mL) and evaporated
to provide the crude acid (7d) (880 mg, quant.) which was used in the
next step without further purification.

[0294]TEA (0.40 mL, 2.9 mmol) was added to the solution of the crude acid
(7d) (880 mg, 2.4 mmol) in THF (10 mL) at -20° C. and the mixture
was treated with isobutyl chloroformate (0.34 mL, 2.6 mmol). After 30
min, an ethereal solution of diazomethane, which was prepared by the
reaction of Diazald (3.0 g, 14 mmol) with KOH (3.0 g, 54 mmol), was
slowly added to the reaction mixture. After stirring the reaction mixture
for 3 h, excess diazomethane was decomposed by careful addition of acetic
acid at 0° C. The reaction mixture was filtered through a short
column of silica gel with the aid of Et2O and concentrated. The
residue was purified by flash column chromatography (hexanes-EtOAc, 4:1)
to provide diazoketone (7e) (800 mg, 86%, two steps).

[0296]Rh2(OAc)4 (27 mg, 0.061 mmol) was added to a solution of
diazoketone (7e) (800 mg, 2.0 mmol) in CH2Cl2 (200 mL). After
stirring for 10 h, the reaction mixture was filtered through a short
column of silica gel with the aid of hexanes-EtOAc (1:1) to remove the
catalyst, and the filtrate was concentrated in vacuo. The residue was
purified by flash column chromatography
(hexanes-acetone-CH2Cl2, 4:1:1) to provide ketone (7f) (480 mg,
65%). Rf 0.29 (hexanes-acetone-CH2Cl2, 4:1:1).

[0334]Methyl ester (9a) (560 mg, 2.6 mmol) was dissolved in MeOH (16 mL)
and 1 N KOH solution (7.9 mL) was added to the solution at 0° C.
The reaction mixture was stirred for 10 min at r.t. and treated slowly
with 2 N HCl (8 mL) at 0° C. After extraction with EtOAc (100
mL×2), the organic phase was dried over MgSO4, filtered and
concentrated. The residue was dissolved in toluene (10 mL) and evaporated
to provide the crude acid (9b) (520 mg, quant.) which was used in the
next step without further purification.

[0335]TEA (0.55 mL, 3.9 mmol) was added to the solution of the crude acid
(9b) (520 mg, 2.6 mmol) in THF (13 mL) at -20° C. and the mixture
was treated with isobutyl chloroformate (0.51 mL, 3.9 mmol). After 30
min, an ethereal solution of diazomethane, which was prepared by the
reaction of Diazald (3.0 g, 14 mmol) with KOH (3.0 g, 54 mmol), was
slowly added to the reaction mixture. After stirring the reaction mixture
for 3 h, excess diazomethane was decomposed by careful addition of acetic
acid at 0° C. The reaction mixture was filtered through a short
column of silica gel with the aid of Et2O and concentrated. The
residue was purified by flash column chromatography (hexanes-EtOAc, 4:1)
to provide diazoketone (9c) (520 mg, 89%, two steps).

[0337]Rh2(OAc)4 (96 mg, 0.22 mmol) was added to a solution of
diazoketone (9c) (1.6 g, 7.1 mmol) in CH2Cl2 (700 mL). After
stirring for 10 h, the reaction mixture was filtered through a short
column of silica gel with the aid of hexanes-EtOAc (1:1) to remove the
catalyst, and the filtrate was concentrated in vacuo. The residue was
purified by flash column chromatography
(hexanes-acetone-CH2Cl2, 4:1:1) to provide ketone (9d) (1.0 g,
71%). Rf 0.16 (hexanes-acetone-CH2Cl2, 4:1:1).

[0354]Platensimycin derivatives of the present invention retain the
backbone structure of platensimycin known as an antibiotic but contain
diverse substituents. The invention includes not only platensimycin
derivatives but also isoplatensimycin and its derivatives, which are
expected to have similar antibiotic activity to platensimycin.
Platensimycin derivates, isoplatensimycin derivatives, platensimycin and
isoplatensimycin can be synthesized, particularly mass-produced, in high
yield and high purity but without side reactions by using the preparing
method described in the present invention.

[0355]In addition, tetracyclo derivatives, the major intermediates for the
production of platensimycin and its derivatives or isoplatensimycin and
its derivatives can be synthesized in high purity and high yield from
tricyclo ketone derivatives prepared by carbonyl ylide [3+2]
cycloaddition according to the present invention.

[0356]Those skilled in the art will appreciate that the conceptions and
specific embodiments disclosed in the foregoing description may be
readily utilized as a basis for modifying or designing other embodiments
for carrying out the same purposes of the present invention. Those
skilled in the art will also appreciate that such equivalent embodiments
do not depart from the spirit and scope of the invention as set forth in
the appended claims.